Faculty Bibliography

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax(®), The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.

BACKGROUND:There is uncertainty regarding the optimal adjunctive unfractionated heparin (UFH) regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with fondaparinux. OBJECTIVE:The aim of this study is to evaluate the safety of 2 dose regimens of adjunctive intravenous UFH during PCI in high-risk patients with NSTE-ACS initially treated with fondaparinux and referred for early coronary angiography. DESIGN/METHODS:This is an international prospective cohort study of approximately 4,000 high-risk patients presenting to hospital with unstable angina or non-ST-segment elevation myocardial infarction, treated with fondaparinux as initial medical therapy, and referred for early coronary angiography with a view to revascularization. Within this cohort, 2,000 patients undergoing PCI will be eligible for enrollment into a double-blind international randomized parallel-group trial evaluating standard activated clotting time (ACT)-guided doses of intravenous UFH versus a non-ACT-guided weight-adjusted low dose. The standard regimen uses an 85-U/kg bolus of UFH if there is no platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitor or 60 U/kg if GpIIb-IIIa inhibitor use is planned, with additional bolus guided by blinded ACT measurements. The low-dose regimen uses a 50 U/kg UFH bolus, irrespective of planned GpIIb-IIIa use. The primary outcome is the composite of peri-PCI major bleeding, minor bleeding, or major vascular access site complications. The assessment of net clinical benefit is a key secondary outcome: it addresses the composite of peri-PCI major bleeding with death, myocardial infarction, or target vessel revascularization at day 30. CONCLUSION/CONCLUSIONS:FUTURA/OASIS 8 will help define the optimal UFH regimen as adjunct to PCI in high-risk NSTE-ACS patients treated with fondaparinux.

BACKGROUND:Major bleeding during an acute coronary syndrome (ACS) is associated with increased late ischemic events. Patients with bleeding are often discharged without antiplatelet therapy (AT). The association between discharge AT use and late ischemic outcomes among ACS patients with bleeding is uncertain. METHODS:We examined discharge AT use among 8,582 ACS patients with in-hospital bleeding from a total of 26,451 patients enrolled in 4 randomized trials. After adjusting for the propensity to receive AT, we compared 6-month postdischarge outcomes between patients discharged with and those discharged without AT. RESULTS:Almost 1 in 10 patients with bleeding was discharged without AT (n=826). Compared with those receiving discharge AT, those not receiving discharge AT had a higher risk of 6-month death, myocardial infarction, and stroke (14.3% vs 7.8%, propensity-adjusted hazard ratio [HR]=1.36, 95% confidence interval=1.01-1.85). Nonuse of AT at discharge was associated with worse outcomes among patients treated with percutaneous coronary intervention compared with those treated without it (adjusted HR=4.22 vs 1.13, interaction P=.0003). Discharge monotherapy was associated with worse outcomes than dual AT among patients receiving stents (adjusted HR=1.78, 95% CI=1.04-3.03). CONCLUSIONS:Bleeding occurred commonly among patients with ACS. AT was often not used in these patients at discharge, and lack of discharge AT was associated with an increased risk of 6-month ischemic events. These data raise the possibility that lack of AT use among patients with in-hospital bleeding may contribute to their excess risk of long-term ischemic outcomes.

The use of glycoprotein IIb/IIIa inhibitors (GPI) reduces ischemic events in patients undergoing percutaneous coronary intervention (PCI). However, the same properties that confer this benefit lead to an increased bleeding risk. Recent studies have shown a less robust net clinical benefit of GPI in the current era of routine thienopyridine and direct thrombin inhibitor use. To optimize the net clinical benefit of GPI, these agents need to be selectively used in patients most likely to benefit from their anti-ischemic effect, namely patients undergoing PCI for non-ST-segment elevation myocardial infarction, select patients undergoing primary PCI, and select patients undergoing PCI without appropriate pre-loading with a thienopyridine. Moreover, strategies to minimize bleeding should be applied in these patients and include shorter GPI infusions (in some patients), dose adjustments of heparin and GPI, careful access site management with more frequent use of the transradial approach, use of smaller sheaths, and identification of patients at high bleeding risk. This review provides an update of the current literature that supports these measures, an insight on the tailored use of GPI, and a potential direction for future research addressing combined antithrombotic therapies.

BACKGROUND:Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells. STUDY DESIGN/METHODS:REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin α on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin α dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin α or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling. CONCLUSION/CONCLUSIONS:The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin α in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

Coronary artery plaque rupture results in platelet adhesion and activation, the release of adenosine diphosphate (ADP), thromboxane A(2), and the generation of thrombin. These factors propagate further platelet activation through a positive feedback mechanism, resulting in the formation of a platelet plug. The treatment of patients with ACS is centered upon the prompt initiation of both antiplatelet and anticoagulant agents. The widespread use of antiplatelet and anticoagulant agents has resulted in a significant reduction in morbidity and mortality but has also increased the risk for bleeding complications. Female gender, advanced age, low body mass index (BMI), low creatinine clearance, and the use of percutaneous coronary intervention have been consistently shown to be risk factors for bleeding. While bleeding was thought to be a necessary side effect and of little clinical significance in the past, it is now clear that bleeding is an independent predictor of adverse ischemic events and mortality. The mechanisms underlying this relationship are not yet fully elucidated and are likely multifactorial (direct effects of bleeding, increased incidence of blood transfusions, less use of antiplatelet agents in both the short and long term). Current treatment guidelines for the use of antithrombotic therapy recommend utilization of evidence-based therapies using clinical strategies shown to minimize the risk of bleeding should when possible. Novel therapies that minimize bleeding risk while providing protection against thrombotic events are needed and may improve outcomes among patients with ACS. Multiple platelet activation pathways and the coagulation cascade regulate hemostasis and thrombosis. Current antiplatelet and anticoagulant therapies for acute coronary syndromes (ACS) act on distinct sites in the pathways for platelet activation and coagulation. While these therapies are effective in reducing the morbidity and mortality associated with ACS, they are associated with a clinically significant increase in the risk of bleeding events. Novel therapies that minimize bleeding risk while providing protection against thrombotic events may improve outcomes in patients with ACS.

OBJECTIVES/OBJECTIVE:The aim of this study was to evaluate practice of transradial approach (TRA). BACKGROUND:TRA has been adopted as an alternative access site for coronary procedures. METHODS:A questionnaire was distributed worldwide with Internet-based software. RESULTS:The survey was conducted from August 2009 to January 2010 among 1,107 interventional cardiologists in 75 countries. Although pre-TRA dual hand circulation testing is not uniform in the world, >85% in the U.S. perform Allen or oximetry testing. Right radial artery is used in almost 90%. Judkins catheters are the most popular for left coronary artery angiographies (66.5%) and right coronary artery angiographies (58.8%). For percutaneous coronary intervention (PCI), 6-F is now standard. For PCI of left coronary artery, operators use standard extra back-up guiding catheters in >65% and, for right coronary artery 70.4% use right Judkins catheters. Although heparin remains the routine antithrombotic agent in the world, bivalirudin is frequently used in the U.S. for PCI. The incidence of radial artery occlusion before hospital discharge is not assessed in >50%. Overall, approximately 50% responded that their TRA practice will increase in the future (68.4% in the U.S.). CONCLUSIONS:TRA is already widely used across the world. Diagnostic and guiding-catheters used for TRA remain similar to those used for traditional femoral approach, suggesting that specialized radial catheters are not frequently used. However, there is substantial variation in practice as it relates to specific aspects of TRA, suggesting that more data are needed to determine the optimal strategy to facilitate TRA and optimize radial artery patency after catheterization.

OBJECTIVES/OBJECTIVE:We examined a large registry to determine the frequency and factors associated with drug-eluting stents (DES) use in saphenous vein graft (SVG) in contemporary practice. BACKGROUND:Prospective trials comparing DES with bare-metal stents in SVG lesions have provided conflicting conclusions regarding safety and efficacy leading to potential variation in stent choice for these lesions. METHODS:We analyzed the frequency and factors associated with DES use in patients undergoing SVG stenting from January 1, 2004, to March 31, 2009, in the National Cardiovascular Data Registry. Generalized estimating equations logistic regression modeling was used to generate independent variables associated with DES use in SVGs. RESULTS:During the study period, percutaneous coronary intervention (PCI) of a SVG represented 5.7% of the total PCI volume (91,355 of 1,596,966). Of the 84,875 patients who received a SVG stent, a DES was used in 64.5%. From 2005 to 2009, DES use in SVG PCI changed from 80% to 62%. Unfractionated heparin was used in 46%, enoxaparin in 17%, bivalirudin in 42%, and a glycoprotein IIb/IIIa inhibitor in 40% of cases. On multivariable analysis, several parameters (including the period, multivessel PCI, prior PCI, no acute myocardial infarction, and no smoking) were associated with DES use. CONCLUSIONS:Currently, DES are used in nearly two-thirds of SVG interventions. Several clinical parameters (such as the period of implantation and the complexity of coronary artery disease) are associated with the decision to implant a DES in these challenging lesions.

BACKGROUND:Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial. METHODS:Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI. RESULTS:Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11). CONCLUSIONS:Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.